KR870000210B1 - The preparation of rhodium catalysts - Google Patents

Abstract

Prepn. of stable homogeneous hydrogenation catalysts comprises reaction of a Rh salt or complex with R'1R'2N.NR'3R'4 (R'1=Ph or benzenesulfonyl, R'2,R'3,R'4=H). The catalysts are useful for the stereospecific hydrogenation of the 6-CH2 gp. in 6-deoxy-6demethyl-6- methylene-5-hydroxytetracycline (I) or its 11a-halo derivs. to give doxycycline in high yield and purity. Since only a small amt. of catalyst is required compared with the prior catalyst, the process is more economic to perform.

Description

Method for producing rhodium catalyst

It is a well known technique that homogeneous catalysts have been used as soluble metal salts since the beginning of the century as a common group that has been known for some time.

The use of d-block transition metals with organic donor ligands is exemplified by Wilkinson et al in the Journal of the Chemical Society 1966,1711-1732 and has a high specific catalytic activity. Eggplant has been published as a catalyst.

An object of the present invention is a catalyst for the hydrogenation of the isocyclic 6-methylene group of 6-deoxy-6-demethyl-6-methylene-tetracycline, even if a small amount of the catalyst is used, high yield and high optical purity This indicates that -6-deoxytetracycline can be obtained.

Among the α-6-deoxytetracyclines, in particular, compounds known as α-6-deoxy-5-hydroxytetracycline, often doxycycline, are well known as antibacterial agents.

One of the important problems common among the prior art in such a process is the simultaneous production of β-epimer.

The presence of such epimers, which cannot be used clinically in effect, requires extensive purification techniques to obtain pure material.

It can be seen from the following that the catalyst used in the present invention is suitable for this purpose. Further details of how to use such catalysts are described in patent application 86-10792, which is filed and pending in this original specification.

Prior arts for such hydrogenation processes are well known and are intended to enumerate only those for particular techniques of the various known methods.

Prior to 1972, only heterogeneous catalysts were known and US Pat. No. 3,200,149 discloses α-6-dec from 6-deoxy-6-demethyl-6-methylene-5-hydroxytetracycline using 5% rhodium carbon. A method for obtaining oxy-5-hydroxytetracycline in a yield of 2496 w / w is described, but the same amount of β-6-deoxy-5-hydroxy citracycline was simultaneously produced and countercurrent distribution).

US Pat. No. 3,444,198 has shown that using 5% palladium on carbon in the presence of catalyst poison such as quinoline-sulfur can improve the yield of α-epimer vs. β-epimer. However, the yields are still low and the need for extensive purification remains.

British Patent No. 1,360,006 relates to the use of a mixed catalyst of hydrazine and carbon palladium, which provides an improved feature of the necessary α-epimer but in which the reaction originates from 11a-chloro intermediates, in which case most impurities This was 6-deoxy-6-demethyl-6-methylene-5-hycitetracycline. As another example the use of raninickel is described in German Patent No. 2,136,62l.

Several patents, such as US Pat. Nos. 3,397,231, 3,795,707, 4,061,676, merely describe new purification technologies. These processes are often long and complex, and it is evident that low purity products are obtained from known processes. In 1972, the first use of a homogeneous catalyst is described in detail in US Pat. No. 4,207,258 and claimed. . The starting material was 11a-unsubstituted tetracyclines and the catalyst was tris (triphenylphosphine) rhodium (1) chloride or several homologues. The content of β-epimer was only about 5%, but the examples describe high yield and improved stereospecificity.

In addition, typical amounts of catalysts were 0.22 parts per part of tetracycline as starting material or 0.024 parts per part of tetracycline as starting material.

U. S. Patent No. 3,962, 331, which was claimed in 1973, was a technology that substantially extends to the scope of U. S. Patent No. 4,207, 258, starting with 11a-substituted tetracyclines. However, β-epimer was still produced at around 5%. For 11a-chloro-6-deoxy-6-demethyl-6-methylene-5-hydroxy tetracycline para-toluene sulfonate, 0.003 per part of starting material. Negative rhodium was used.

In 1973, French Patent No. 2,216,268 described the use of the same catalyst and the hplc fraction of the reaction mixture of a typical example had a ratio of α-epimer to β-epimer of 92: 8. This patent requires a catalyst comprising 0.13 parts of rhodium per 1 part of 6-deoxy-6-demethyl-6-methylene-5-hydroxytetracycline to be hydrogenated.

U.S. Patent No. 3,954,862 describes a technique using rhodium on carbon by mixing a tertiary phosphine with an accelerator such as hydrochloric acid.

It can be seen that this mixture is capable of producing the soluble rhodium complex salts described in the three patents, in the presence of a solvent such as methanol. Typical examples show that 1-5% of unwanted β-epimers are formed. The use of 0.019 parts yielded a product containing 45% of the starting material, and by continuing to hydrogenate using more than 0.019 parts, about 15% of the starting material remained in the product. U. S. Patent No. 3,907, 890 describes a process using cobalt octacarbonyl, triphenyl phosphine and hydrochloric acid. Since it is not a hydrogenation reaction, hydrogen was not added per se, and the reaction produced the amount of β epimer in the range of 17% to 0.5%.

Thus, the stoichiometric yield varied from 54-72%. Overall, the process showed a lot of changes in yield and purity.

U.S. Patent No. 4,001,321 typically uses dicarboxylate (triphenylphosphine) rhodium (II) as a catalyst, typically 6-deoxy-6-deethyl-6-methylene-5-hygisitete 0.01 part of rhodium per cyclone was used, and the product contained 2-3% of β-epimer.

Finally, U. S. Patent No. 3,962, 131 uses an uncut catalyst prepared by reacting 1 mole of rhodium trichloride with 2 moles of sodium acetate and finally with triphenylphosphine.

Unfortunately, there is no rhodium analysis for the catalyst obtained, but assuming that rhodium is included as a catalyst from the beginning, about 0.003 parts of rhodium per 6-deoxy-6-demethyl-6-methylene-5-hydroxytetracycline are required. Is calculated. Moreover, the content of β-epimer was unknown because there was no chromatographic analysis.

Therefore, it can be easily seen that the need for a catalyst capable of satisfying the following conditions is required. In other words,

1. Use 0.001 parts or less of catalyst per part of tetracycline to be hydrogenated,

2. The hydrogenated product is prepared in high yield,

3. It should be generated to prevent or almost neglect the generation of unnecessary β-epimer.

Several catalysts are being devised which can meet this need and according to the invention, rhodium salts or rhodium complexing compounds and triphenylphosphine are hydrazines having a structure of R ' ₁ R' ₂ N.NR ' ₃ R' ₄ or Salts thereof, wherein R ' ₁ is a phenyl or benzenesulfonyl group or hydrogen and R' ₂ , R ' ₃ and R' ₄ are hydrogen, wherein the reaction consists of a process of reacting in the presence or absence of excess triphenylphosphine; It is to provide a process for producing a stable rhodium homogeneous hydrogenation catalyst. In this case, the rhodium salt is carried out in an organic solvent in the presence of an excess of triphenylphosphine and in the organic solvent at reflux temperature of the reaction medium until the reaction is completed, and then a non-solvent capable of mixing the catalyst mentioned therein. It is obtained by the method of addition, isolation, and filtration.

In addition, the catalyst of the present invention has a very advantageous position not only in the field of tetracyclines but also in fields requiring other stereospecific homogeneous catalysts.

Unfortunately, most of the catalysts of the present invention have no known structural analysis because the crystal size is not suitable for analysis by crystals or X-ray crystallography.

But by applying other analytical techniques, their patentability could be confirmed without question.

These catalysts can be prepared by various methods. That is, it can be obtained by reacting a rhodium complex with hydrazine or by reacting a rhodium salt with hydrazine or its salts, all of which are carried out in the presence of triphenyl phosphine.

In the first case, the rhodium complex is one of a complex of rhodium and triphenylphosphine and a suitable rhodium complex is tris (triphenyl phosphine) chlorodium (I).

The hydrazine to be reacted with the complex has the general structure of R ' ₁ R' ₂ N.NR ' ₃ R' ₄ , wherein R ' ₁ is a phenyl, benzenesulfonyl group, or hydrogen and R' ₂ , R ' ₃ and R ₄ is hydrogen. Preferred hydrazines are hydrazines themselves, and preferred are hydrates.

In general, hydrazine should be in excess of the number of moles of rhodium present in the reaction, where excess means an excess from slightly more than 100 moles to the same number of moles. It is preferable to use 3 moles of hydrazine per mole of rhodium, and the effect of using the catalyst is the same even if an excess of 50 moles per mole is used.

This process is carried out in the presence of triphenylphosphine.

U. S. Patent No. 3,463, 830 describes adducts other than compounds for this reaction, wherein triphenylphosphine is a compound of palladium and platinum in which hydrazine and excess tertiary phosphine are present in the presence of zero-valent palladium and platinum 3 It was shown to change to a class phosphine complex.

In addition, this patent demonstrated that excess tertiary phosphine is reduced from the reaction of coordination unsaturated palladium and platinum tertiary phosphine complexes.

Therefore, the method for preparing a novel catalyst included in the present invention has more than 20 moles of triphenylphosphine per mole of rhodium present in the reaction, with or without trphenylphenyl phosphine. Typically 3-15 moles / mole are suitable.

The reaction medium may be selected from lower alcohols or cyclic ethers which may surround the glycol.

Representative examples of those suitable as solvents include methanol, ethanol, furopanol, furanpan-2-ol, butanol, 2-methyl-furopan-2-ol, ethane-1,2-diol and methanol, ethanol, furopan- Tetra hydrofuran or butanol containing 2-ols are most suitable.

The reaction is conducted at 0 ° C.-100 ° C. but a suitable temperature is between about 90 ° C. at room temperature.

Typically, the reaction is carried out at room temperature, but by increasing the temperature, the reaction can proceed more quickly.

The initial color of the reaction mixture is purple and the color of the catalyst of the present invention is always orange and yellow and brown, the reaction can be carried out while visually confirming.

Therefore, it can be easily determined that the time required for the reaction depends on the temperature.

Typically it is between two hours in a few minutes.

The catalyst can be prepared by the above method, but it is suitable to use an inert gas such as nitrogen. When it is determined that the reaction is completed, the catalyst can be obtained by a conventional known method.

In general, when the catalyst is not dissolved or the catalyst does not react by adding an organic solvent, filtering or washing with the same organic solvent may be selected in a method.

Suitable organic solvents are diisoprophyl ethers.

It can be seen from some examples that the catalyst of the present invention is insoluble in the reaction mixture and in this case can be obtained by simple filtration or washing.

Next, the catalyst is dried at room temperature.

It is a feature of the present invention that the catalyst can be used without preparation and isolation.

Therefore, rhodium triphenylphosphine complexes and hydrazine are mixed in a suitable organic solvent in the presence of triphenylphosphine and stirred at the required temperature until there is a change in color indicating completion of the reaction.

Next, 6-deoxy-6-demethyl-6-methylene-5-hydroxytetracycline or 11a-halo homologue was added, and as needed solvent and triphenylphosphine were added.

The mixture was then hydrogenated in the usual way to afford the desired product. Such a process is described in more detail in our split application (Patent Application 86-10792).

As noted above, the catalysts can be prepared from rhodium salts, hydrazines or their salts and triphenylphosphine in suitable solvent mixtures.

As the rhodium salt, a trihydrate form of rhodium trichloride is suitable.

Hydrazine has the general structure of R ' ₁ R' ₂ N · NR ' ₃ R' ₄ , wherein R ' ₁ , R' ₂ , R ' ₃ and R' ₄ are as mentioned above and more suitably Phenylhydrazine, benzenesulfonylhydrazine and their salts.

Very suitable are hydrazine hydrate and hydrazine dihydro chloride.

Hydrazine is usually present in excess of the amount of rhodium in the reaction and is about 10 moles relative to the molar ratio of atmospheric rhodium.

Usually triphenylphosphine is present in excess relative to the molar amount present in rhodium, with a range of about 1-2.5 moles / mole being particularly suitable.

The reaction medium is a mixture of water and organic solvent which are inert to the reaction.

"Inert in the reaction" in this case means that it does not chemically react with the resulting catalyst.

This means that molecules of this type, as known in the art, cannot readily substitute coordination ligands.

Thus, the organic solvent is a lower dialkyl ketone such as acetone and butan-2-one, or ethanol, ethanol, furopanol, propan-2-ol, butanol, 2-ethyl-furopan-2-ol and ethane-1,2-diol. Lower alcohols such as glycols, ethers such as tetrahydrofuran, lower dialkylamides such as dioxane, dimethyl formamide or organic nitriles such as acetonitrile.

The most suitable organic solvent is acetone.

This reaction is carried out between 0 ° C. and the complete temperature of the reaction medium and is best carried out between 50 ° C. and 80 ° C.

If the reaction temperature is 0 ℃ or less, the reaction is too slow, which is not practical. The reaction time is typically between 1-5 hours, although it is always about 3 hours.

As mentioned above, it is suitable to use an inert gas, such as nitrogen, to prepare the catalyst. In this process the catalyst is always insoluble in the reaction mixture and thus can be obtained by simple methods such as filtration. It can be seen from a number of examples that the catalyst of the present invention is advantageous in that the catalyst does not dissolve upon addition of a solvent that can be dissolved but mixed in the reaction mixture.

The solvent should not react with the resulting catalyst, especially with di-isofurophylether.

After filtration the catalyst is always washed with a suitable organic solvent such as diethyl ether and dried at room temperature.

Another excellent method in the present invention is that rhodium salts such as rhodium trichloride trihydrate can be reacted with hydrazine without the addition of triphenylphosphine.

Hydrazine in hydrate form is present in excess in this reaction and is usually about 10 moles in the molar ratio of rhodium present.

Compared with the conventional method, water is mixed with an organic solvent which may be selected from the following to make a reaction medium: lower dialkyl ketone; Lower alcohol; Ether; Organic nitrile; Or lower dialkylamides and those mentioned above.

Suitable solvent is acetone.

The suitable temperature range is 50-80 ° C. and the reaction time is about 1-5 hours but suitably about 3 hours.

The novel compounds obtained in this way are similar to those already mentioned and should be filtered upon addition of an organic solvent when the compounds are insoluble in the reaction mixture.

The solvent must not react with the product in any way and a suitable solvent is di-isofurophyl ether. It will be shown that the presence of tertiary phosphines is required to hydrogenate these compounds as catalysts. More than this technique is described in more detail in our divided and pending patent application specification (Patent Application 86-10792).

Naturally, the amount of rhodium in which the mother liquor remains in the preparation of the catalyst can be recovered by a universal method easily and practically without loss, and can be recycled and used.

As mentioned earlier, the structure of this novel catalyst could not be explained by X-ray crystallography because it could not obtain crystals of sufficient size, but could be analyzed by other techniques.

The main difference between the prior art and the catalyst of the invention is explained by the I R spectrometry.

Wilkinson catalyst Tris (triphenylphosphine) chlorodium (I), shows a peak at the following position:

5.80 (s); 6.00 (s); 6.76 (m); 7.00 (m); 7.65 (m); 8.45 (m); 8.65 (m); 9.20 (m); 9.73 (ms); 10.20 (s); 13.50 (l, b); 14.40 (l, b) microns where s, m, l represent small, medium and large peaks and b stands for broad.

The catalyst of the present invention has a broad medium peak at about 6.3 microns.

Comparative spectroscopy of the catalysts showed that these peaks were not present in the Wilhelmson catalyst.

Elemental analysis of the catalysts showed a marked difference as expected.

Therefore, the nitrogen content, depending on the actual catalyst, is about 2% -6% but mostly 4%.

Most catalysts are sensitive to oxygen and require great care in their analysis.

Sensitive to oxygen can be seen as the color turns brown.

In general, the content of rhodium is 10-18%, usually about 14%. From the results obtained through the experiment, it was estimated that the catalyst had the following structural formula prepared from the starting material containing chlorine.

(PPh ₃ ) _χ (R ' ₁ R' ₂ N.NR ' ₃ R' ₄ ) _y Rh _z Cl _z

Here, the presence of the z atom of rhodium in each molecule means the possibility of generating a two- or three-molecular compound.

However, although the assumed general formula has not yet been confirmed by X-ray crystallography, it cannot be concluded that this is wrong.

The following examples specifically illustrate the invention and do not limit the invention.

Example 1

A) Catalyst: Tris (triphenylphosphine) chlorodium (I) (3.00 g: 3.24 mmol) was added to a solution in which hydrazine hydrate (0.48 mmol: 9.88 mmol) was dissolved in 95% ethanol (60 mmol).

The mixture was refluxed with nitrogen for 25 minutes until the purple changed to orange.

The solid crystal obtained by cooling was filtered, washed with diisopuro ether, and dried to obtain 1.40 g of a yield.

Additional amounts were obtained by adding diisopurophyl ether to the mother liquor and concentrating at low temperature.

The I R spectrum showed a broad peak at 6.30 microns. Elemental analysis showed the product to contain 16.95% rhodium and 4.25% nitrogen.

B) Hydrogenation: The catalyst (25 mg) obtained in Example 1A was treated with 6-deoxy-6-demethyl-6-methylene-5-hydroxytetracycline hydrochloride (MOT.HC1; 7.38 g; 15.41 mmol). Phosphine (0.1 g: 0.38 mmol) was added to a stainless steel dehydrogenation reaction vessel containing a solution dissolved in methanol (40 mmol) together with methanol (20 mmol) under magnetic stirring. After purging with nitrogen, hydrogen was added at a pressure of 8 kg / cm ² and the mixture was heated to 89 ° C.

Consumption was dropped for 5 hours 30 minutes and cooled after 1 hour.

The reaction mixture was filtered through a G4 glass filter and p-toluene sulfonic acid (3.30 g: 19.16 mmol) was added with stirring to the filtrate.

Thus produced α-6-deoxyoxytetracycline p-toluenesulfonate was filtered, washed with acetone and dried.

9.65 g of fresh water showed the following analysis results: Humidity 3.13%, yield 98.4% Purity 99.8% by anhydrous state by Karl Fitser method.

No epimers or starting materials were detected by circulatory paper chromatography ("Schleicher & Schull" paper Nr. 2045B, 265 mm, ref. Anhydrous disodium phosphate was mixed to form a buffer at pH 3.5; mobile phase: nitromethane, chloroform, pyridine-: 20: 10: 3)

Example 2

Instead of 25 mg of catalyst, 15 mg was added and Example 1B was repeated.

α-6-deoxyoxytetracycline p-toluenesulfonate 8.57 g yield 90%.

0.45% of β-epimer and traces of starting material were included.

Example 3

A) The catalyst (15 mg) obtained in Example 1A was converted to methanol (40 ml) in 11a-chloro-6-dioxy-b-demethyl-6-ethylene-5-hytetracycline p-toluenesulfonate (10.0 g). : 15.41 mmol) and triphenylphosphine (4.00 g: 15.25 mmol) were added together with ethanol (20 ml) to a stainless steel hydrogenation reactor containing a solution.

It was then flushed with nitrogen and filled with hydrogen at 88 ° C. under a pressure of 9.2 kg / cm ² .

After 9 hours 30 minutes, the mixture was cooled and the reaction mixture was filtered. The filtrate was added with p-toluenesulphonic acid (3.30 g: 19.16 mmol) and the mixture was stirred for 2 hours. The resulting crystals were filtered off and washed.

Yield 84.2% yielded 8.0 g of α-6-deoxyoxytetracycline p-toluenesulfonate. No β-epimer or starting material was detected in the circulating chromatography in the product.

B) 7.82 g of α-6-deoxyoxytetracycline p-toluenesulfonate was obtained in 82.3% yield by repeating Example 3A using the same catalyst at 10 mg.

Example 4

A) Catalyst: The reaction mixture was stirred at room temperature (28 ° C.) for 90 minutes. Except for the above, the conditions in Example 1A were repeated. As the first fraction, 1.63 g of orange material was obtained.

The mother liquor was concentrated under a low temperature major to obtain 1.22 g or more.

The I R spectrum showed a browood peak at 6.3 microns.

B) Hydrogenation: The reaction mixture (0.50 ml) obtained in the preceding paragraph was used as catalyst for the hydrogenation process described in Example 1B. 8.82 g of isolated α-6-deoxyoxytetracycline-p-toluenesulfonate was obtained with a yield of 92.8%.

No circular paper chromatography was detected for the β-epimer or starting material.

Next, the mother liquor was diluted with the same amount of water and sulfosalicylic acid (4.0 g: 18.33 mmol). This resulted in incidentally obtaining 0.83 g of doxycyclinesulfosalicylate containing 10% β-epimer.

Example 5

A) Catalyst: The solvent of methanol was used and the reaction time was 20 minutes, and the conditions of Example 4A were repeated.

The first fraction gave 1.40 g of a light brown filtrate (solid).

Concentration by addition of diisopropyl ether yielded two or more fractions of 1.59 g in total. The browood park in the I R spectrum was at 6.30 microns.

Elemental analysis revealed that the first fraction contained 15.53% rhodium and 2.52% nitrogen.

B) Hydrogenation: The reaction mixture of the preceding paragraph (0.5 ml) was used as catalyst in the hydrogen difference reaction process of Example 3A.

Doxycycline p-toluenesulfonate was obtained by doing so by 8.27 g and yield 87.1%.

Specific light intensity (methanol with 1% hydrochloric acid) was -77.5 °.

Example 6

A) Catalyst: The conditions of Example 4A were repeated using propan-2-ol as solvent.

In this case, the mixture was stirred for 45 minutes before filtering the orange product.

The yield of the first fraction was 64% W / W, 30% W / W was further obtained by adding diisopurophyll ether, concentrating and filtering.

Browwood peak was at 6.30 microns in I R spectrum.

B) Hydrogenation: The hydrogenation process described in Example 1B was repeated using the catalyst (25 mg) obtained above.

α-6-deoxyoxytetracycline is isolated with 8.83 g of p-toluenesulfonate and the analysis results are as follows:

The humidity was 0.11% (Kalfitshire method), yield 92.82% and purity 99.9% in anhydrous state.,

Example 7

In Example 6A, a stainless steel dehydrogenation reactor containing a solution of 6-deoxy-6-demethyl-6-methylene-5-hydroxytetracycline hydrochloride (7.38 g; 15.41 mmol) in ethanol (40 ml) was dissolved. The obtained catalyst (25 mg) was dissolved in methanol (20 ml) and added.

Hydrogenation and isolation were carried out as in Example 1B.

This gave 8.17 g of α-6-deoxyoxytetracycline p-toluenesulfonate having the following analysis:

Humidity 2.18% by Karl Fischer method, yield 84.1% in anhydrous state, purity 99.2%.

Example 8

A) Catalyst: 1.43 g of orange product was obtained by using n-butanol and the reaction time of 20 minutes under the conditions of Example 4A.

The second fraction was obtained in the usual way. In elemental analysis, rhodium content was 18.32% and nitrogen content was 6.21%.

B) Hydrogenation: The catalyst (25 mg) and methanol (20 ml) obtained here were added to a stainless steel hydrogenation reactor containing a solution of 15.41 mmol) and triphenylphosphine (0.25 g; 0.95 mmol) dissolved in ethanol (10 ml). It was.

Hydrogenation and isolation were carried out as in Example 1B. 9.95 g of α-6-deoxyoxytetracycline p-toluenesulfonate having the following analysis result was obtained:

Β-epimer or starting material was not detected in 5.32% of drying loss, 99.14% of yield in dry state and 99.89% of purity.

Example 9

A mixture of tris (triphenylphosphine) chlorodium (I) (1.00 g: 1.08 mmol) and hydrazine hydrate (2.50 ml; 51.4 mmol) in n-butanol (40 ml) was heated at 90 ° C. for 25 minutes.

Di-isopuropropyl ether was added to the cooled reaction mixture to obtain 0.25 g of a yellow solid.

Further fractions can be obtained by further adding di-isofurophyl ether.

Example 10

Tris (triphenylphosphine) chlorodium (I) (1.00 g; 1,08 mmol) and hydrazine hydrate (0.16 ml: 3.29 mm: 1) were refluxed with 20 ml of ethanol for 20 minutes.

The color changed from red to yellow.

Triphenylphosphine (3.00 g: 11.44 mmol) was added at this point and reflux was continued for 20 minutes or more.

Filtration after cooling at room temperature gave a brown product.

The product showed a browood band at 6.30 microns with an I R spectrum.

Example 11

A) Catalyst: Tris (triphenylphosphine) chlorolodium (I) (1.00g; 1.08mmol) dissolved in phenylhydrazine (0.32ml: 3.25mmol) in acetonitrile (20ml) at 65 ° C under nitrogen gas. Heated for minutes.

Beige solids were selected by cooling the solution, diluting with diisopurofylether and then filtering. The yield is 25% W / W including the mother liquor containing the product.

The brood pig again appeared at 6.30 microns on the I R spectrum.

B) Hydrogenation: Example 1B was repeated using the catalyst (25 mg) obtained in Example 11A.

α-6-deoxyoxyoxy tetracycline p-toluenesulfonate was obtained in 8.33 g and yield 87.6%.

Cycla paper chromatography also did not include starting material and β-epimer.

Example 12

A) Catalyst: Rhodium trichloride trihydrate (1.00 g; 3.80 mmol) was dissolved in water (5.0 ml) and heated to 70 ° C. for 1 hour.

Triphenylphosphine (1.95 g; 7.43 mmol) was added to a solution of acetone (25.0 ml) over 20 minutes under nitrogen gas.

After stirring for 10 minutes or more, hydrazine hydrate (1.90 m; 39.09 mmol) was added thereto, and the mixture was refluxed for 3 hours and then stirred at 45 ° C. for 1 hour.

The crystalline solid was filtered off, washed with a small amount of acetone and finally with di-ethyl ether to give 1.05 g of an orange solid.

Brodpeaks appeared at 6.30 microns on the I R spectrum.

Elemental analysis was 12.43% rhodium and 2.61% nitrogen.

B) Hydrogenation: A solution obtained by dissolving the obtained catalyst (17 mg) in methanol (13.5 ml) was added to a stainless steel hydrogenation reactor containing a solution dissolved in methanol (27 ml). Hydrogenation was carried out at 88 ° C. and pressure 8-9.2 kg / cm ^{2 for} 6 hours 30 minutes.

p-toluenesulphonic acid (2.23 g: 12.95 mmol) was added to the filtered reaction mixture and stirred for 2 hours. The crystals obtained were then filtered, washed with acetone and dried.

The product was obtained in 5.4 g, yield 83.9%.

By circular paper chromatography, it was found that β-epimer was contained in trace amounts. The mother liquor was then diluted with the same amount of water and sulfosalicylic acid (4.0 g; 18.33 mmol) was added. Cracking yielded 0.47 g of sulfosalicylate of doxycycline, having 8% β-epimer and about 2% degradation products.

Example 13

Triphenylphosphine (68 mg: 0.26 mmol) was added to the reaction mixture before hydrogenation and Example 12B was repeated. In this manner, α-6-deoxyoxytetracycline p-toluene sulfonate was obtained at 5.36 g and yield 83.3%. This included trace amounts of β-epimer. Secondly, 0.7 g of sulfosalicylate was obtained, which contained 4% of β-epimer.

Example 14

Rhodium trichloride trihydrate (0.50 g; 1.90 mmol) was dissolved in water (2.5 ml) by heating at 70 ° C. for 1 hour.

Next, a solution in which acetone (12.5 ml) dissolved triphenylphosphine (0.73 g; 2.78 mmol) was added under nitrogen pressure for about 20 minutes. The mixture was stirred for 10 minutes after the addition of hydrazine hydrate (0.95 ml; 19.55 mmol).

The mixture was refluxed for 3 hours and stirred at 45 ° C. for 1 hour.

Filtration, washing with a small amount of acetone and washing with di-ethyl ether again gave a yellow product.

Yield 58%.

Example 15

A) Catalyst: Rhodium trichloride trihydrate (0.5 g; 1.90 mmol) was added to water (2.5 ml) and stirred for 1 hour at 70 DEG C while stirring and hydrazine hydride (0.8962 ml; 18.44 mmol) was added to acetone (9.24 ml). Was added.

It was refluxed for 3 hours, then cooled and the crystals filtered.

B) Hydrogenation: Hydrogenation was carried out as described in Example 1B using the catalyst (25 mg) obtained above. In this manner, 7.96 g of α-6-deoxyoxytetracycline p-toluenesulfonate was obtained in a yield of 83.3%. It contained about 1.5% β-epimer. The mother liquor was then diluted with the same amount of water and Sulphosalicylicacid (4.0 g; 18.33 mmol) was added.

Incidentally, 1.55 g of doxycyclinesulfosalicylate containing 93% of α-epimer and 7% of β-epimer was obtained incidentally.

Example 16

Example 15B was repeated without adding triphenylphosphine to the hydrogenation reaction mixture.

There was no consumption of hydrogen and 6-deoxy-6-demethyl-6-methylene-5-hydroxytetracycline remained unchanged.

Example 17

A) Catalyst: Example 12A was repeated replacing hydrazine hydrate with phenylhydrazine (3.85m: 39.1 mmol).

2.10 g of a yellowish orange product were obtained, with a brood peak of 6.30 microns in an I R spectrum.

B) Hydrogenation: Example 1B was repeated using the catalyst (25 mg) obtained above, yielding 8.50 g of (alpha) -6-deoxyoxy tetracycline p-toluenesulfonate with a yield of 89.4%.

Example 18

A) Catalyst: Rhodium trichloride trihydrate (0.50 g; 1.90 mmol) was added to water (2.5 ml) and butan-2-one (12.5 ml) was added to a solution containing triphenylphosphine (0.98 g; 3.74 mmol). After 20 minutes or more, the solution was heated and dissolved at 70 ° C for 1 hour.

The mixture was stirred for 10 minutes under nitrogen gas. Benzenesulfonylhydrazine (3.37 g; 19.57 mmol) was added and the mixture was stirred at 67 ° C. for 3 hours and at 45 ° C. under nitrogen gas for 1 hour.

The cooled reaction mixture was filtered to yield 0.93 g of orange product.

The peak in the I R spectrum was at 6.30 microns.

B) Hydrogenation: Example 1B was repeated using the above catalyst (25 mg).

In this manner, 8.57 g of α-6-deoxyoxytetracycline p-toluenesulfonate was obtained in a yield of 90%. No β-epimer or starting material was detected by circular paper chromatography.

B) Hydrogenation: A solution obtained by dissolving the catalyst (25 mg) obtained above in methanol (20 ml) was dissolved in 11a-chloro-6-deoxy-6-dimethyl-6-methylene-5-hydroxytetricycline p-toluene sulfonate (10.00 g (15.41 mmol) and triphenylphosphine (4.00 g; 15.25 mmol) in methanol (40 ml) were added to a stainless steel hydrogenation reactor containing a solution.

After washing with nitrogen, hydrogen was filled at a pressure of 9 kg / cm ² , 88 ° C.

After 6 hours 30 minutes the hydrogenation reactor was cooled and the mixture was filtered.

p-toluene sulfonic acid (3.3 g; 19.16 mmol) was added to the filtrate and stirred for 2 hours.

The crystals were filtered off, washed with acetone and dried.

α-6-deoxyoxyoxytetracycline p-toluenesulfonate was obtained in 8.27 g and yield 87.0%.

No β-epimer or starting material was detected by circular paper chromatography.

Example 19

Rhodium trichloride trihydrate (0.50 g; 1.90 mmol) was added to water (2.5 ml) and dissolved by heating at 70 ° C. for 1 hour.

A solution of triphenylphosphine (0.975 g: 3.72 mmol) and hydrazine dihydrochloride (2.05 g; 19.53 mmol) was added to acetone (12.5 ml) under nitrogen gas for 20 minutes.

After stirring for 10 minutes, the mixture was refluxed for 3 hours. Cooling gave the product as creamy crystals. After filtration, washing with a small amount of acetone, and again with diethyl ether to give 1.05 g.

Example 20

Rhodium trichloride trihydrate (0.50 g; 1.90 mmol) was dissolved in water (2.5 ml) by heating at 70 ° C. for 1 hour.

A solution of methanol (12.5 ml) and triphenylphosphine (0.975 g; 3.72 mmol) was added under nitrogen for 20 minutes. After stirring for 10 minutes, hydrazine hydrate (0.95 ml; 19.55 mmol) was added and the mixture was refluxed under nitrogen for 3 hours.

A solid consisting of cooling crystals was obtained. This was selected by filtration, washing with a small amount of methanol and finally washing with diethyl ether. 0.57g of orange solids were obtained.

Example 21

A) Catalyst: When hydrazine hydrate (8 μl; 0.16 mmol) is suspended in a solution of tris (triphenylphosphine) chlorodium (I) (50 mg: 0.05 mmol) and ethanol (10 ml) and the mixture is changed in color at room temperature. Stir for a few minutes.

B) Hydrogenation: 11a-chloro-6-deoxy-6-dimethyl-6-methylene-5-hydroxytetracycline p-toluenesulfonate (20.0 g; 30.81 mmol) and triphenylphosphate without isolating the above catalyst To a solution of pin (8.00 g: 30.50 mmol) in methanol (105 ml) was added.

Subsequently, the mixture was hydrogenated at a pressure of 8 kg / cm ² and a temperature of 87 ° C-98.5 ° C for 6 hours.

The mixture was then cooled to 45 ° C. and added with stirring p-toloenesulphonic acid (6.7 g: 38.91 mmol). After stirring for 2 hours or more, the mixture was cooled to 0 ° C. This was then filtered, methane washed with (2 x 5.5 ml) and acetone (2 x 5.5 ml) and dried.

α-6-deoxyoxytetracycline p-toluenesulfonate was obtained in 17,23 g and yield of 90.7%.

The content was 0.3% β-epimer and hplc (column: μBondapak "Waters" CN-ref.No. PN 84042 S / N; solvent: 80% tetrahydrofuran, 80% water and 20% acet in 0.001M EDTA A 20% mixture of ticacides: flow rate: 2.5 ml / min; detection: UV268 nm; 1.0 AuFS; chart: 5 mm / min) showed no starting material.

Example 22

A) Catalyst: Hydrazine hydrate (0.08 ml: 1.65 mmol) was added to a solution of tris (triphenylphosphine) chlorodium (I) (0.5 g: 0.54 mmol) and propan-2-ol and refluxed for 25 minutes.

It was then cooled and filtered.

Thus, a catalyst containing 14.1% rhodium was obtained.

B) Hydrogenation: Example 18C was repeated using the catalyst (25 mg) obtained above.

Isolated α-6-deoxyoxytetracycline p-toluenesulfonate was obtained in 8.02 g, yield 84.4%. It was found that β-epimer or starting material was not detected by Cycla paper chromatography.

Example 23

A) Catalyst: Rhodium trichloride trihydrate (0.5 g; 1.90 mmol) was heated to 70 DEG C under molar (2.5 ml) at 70 DEG C for 1 hour.

Triphenylphosphine (0.975 g; 3.72 mmol) was then added to butan-2-one (12.5 ml) followed by hydrazine hydrate (0.95 ml; 19.55 mmol). After refluxing for 3 hours, the mixture was stirred at 45 ° C. for 1 hour, then cooled, the crystals were washed by filtration and dried.

B) Hydrogenation: Example 18C was repeated using the catalyst (25 mg) obtained above to give an α-6-deoxyoxytetracycline p-toluenesulfonate mold 8.04 g, yield 84.6%.

It was found that β-epimer and starting material were not detected by Cycla paper chromatography.

Example 24

A) Catalyst: Methanol solution of hydrazine hydrate (0.394ml / 100ml solution 0.6ml) was stirred with tris (triphenylphosphine) chlorodium (I) (15mg; rhodium content 11.0%) and methanol (20ml) solution Was added.

Stirring continued for several minutes until there was a change in color.

B) Hydrogenation: The reaction mixture of the catalyst described above was converted to 11a-chloro-6-deoxy-6-demethyl-6-methylene-5-hydroxy tetracycline p-toluenesulfonate (10.0 g; 15.41 mmol) and triphenylphosphate. A stainless steel hydrogenation reactor containing pin (4.00 g; 15.25 mmol) and methanol (40 ml) was added.

After washing with nitrogen, hydrogenation was carried out at 9.2 kg / cm ² , 88 ° C. for 9 hours.

Then it was cooled and filtered.

Subsequently, p-toluenesulphonic acid (3.3 g: 19.16 mmol) was added, the mixture was stirred for 2 hours, and then filtered. The yield of 6-deoxyoxytetracycline p-toluenesulfonate produced in this way was 85.9%, obtaining 8.16 g. It was found that β-epimer was not detected by Cycla paper chromatography, but traces of starting material were present.

Claims (12)

A rhodium salt or a rhodium complexed compound and triphenylphosphine are reacted with hydrazine or a salt thereof having a structure of R ′ ₁ R ′ ₂ N · NR ′ ₃ R ′ ₄ , wherein R ′ ₁ is a phenyl or benzenesulfonyl group or hydrogen R ' ₂ , R' ₃ and R ' ₄ are hydrogen, in which the reaction is a step of reacting in the presence or absence of excess triphenylphosphine, in the case of rhodium salt in the presence of an excess of triphenylphosphine, from 0 ° C. to reaction Process for producing a new and stable homogeneous rhodium hydride catalyst, which is carried out in an organic solvent at the reflux temperature of the medium until the reaction is completed, and then is isolated and filtered by adding a nonsolvent which can be mixed with the catalyst obtained. . The process according to claim 1, wherein the rhodium complexing compound to react with hydrazine is tris (traphenylphosphine) chlorodium (I). The method according to claim 1, wherein the hydrazine is hydrazine itself and is of a monohydrate type. The process according to claim 1, wherein the organic solvent is lower alcohol or cyclic ether. The rhodium salt of claim ₁ is reacted with a hydrazine or a salt thereof having a structure of R ′ ₁ R ′ ₂ N · NR ′ ₃ R ′ ₄ , wherein R ′ ₁ is a phenyl or benzene sulfonyl group or hydrogen and R ′ _2, R _'3 and R' ₄ is hydrogen, triphenyl under the pin is present, at the reflux temperature of the mixture of the organic solvent is inert in water and reaction, 1 20 ℃ for 5 hours to the reaction medium after reaction was filtered Or a non-solvent and filtered. The production method according to claim 5, wherein the rhodium salt is rhodium trichloride and is in trihydrate form thereof. 6. The process according to claim 5, wherein the hydrazine is hydrazine itself, phenylhydrazine, benzenesulfonylhydrazine and salts thereof. The method of claim 5, wherein the hydrazine is present in stoichiometric excess. The process according to claim 5, wherein 1 to 2.5 moles of triphenylphosphine are used per mole of rhodium present. 6. The process according to claim 5, wherein the organic solvent is lower di-alkyl ketone, lower alcohol, ether, organic nitrile or lower di-alkylamide. The process according to claim 4, wherein the lower alcohol is methanol, ethanol, furopan-2-ol, butanol or 2-ethylfurophan-2-ol, and cyclic ether is tetrahydrofuran. The lower di-alkyl ketone of claim 10, wherein the lower di-alkyl ketone is acetone or butan-2-one, and the lower alcohol is methanol, ethanol, furopanol, furopan-2-ol, butanol, or 2-methylfuropan-2-ol. , Ether is tetrahydrofuran or dioxane, organic nitrile is acetonitrile and lower di-alkyl amide is dimethylformamide.